Environmental stresses converge on the mitochondria that can trigger or inhibit cell death. Excitable, post-mitotic cells (such as cardiac myocytes in heart, and neurons in brain), in response to sub-lethal noxious stress engage mechanisms affording protection from subsequent insults. These protection mechanisms involve activation of endogenous signaling which can confer significant resistance to oxidant and other stresses associated with hypoxia/reoxygenation (i.e., during a heart attack or stroke), which promotes the enhanced capacity for cell survival. However, the upstream signaling mechanisms have remained an area of active debate, and the end effector(s) have remained unsolved. We show that reoxygenation after prolonged hypoxia reduces the reactive oxygen species- (ROS-) threshold for the mitochondrial permeability transition (MPT) in cardiac myocytes, and that cell survival is steeply negatively correlated with the fraction of depolarized mitochondria. We demonstrate that a wide variety of cardio/neuroprotective agents acting via distinct upstream mechanisms all promote cell survival by limiting MPT induction. We found that protection can be triggered in 2 general ways ? dependent and independent of regulatory mitochondrial swelling ? which converge via inhibition of GSK-3beta on the end effector, the permeability transition pore complex, preventing the MPT. Cell protection exhibiting a memory (preconditioning) results from triggered mitochondrial swelling causing enhanced substrate oxidation and ROS production, leading to redox activation of PKC which inhibits glycogen synthase kinase-3beta (GSK-3beta). Alternatively, receptor tyrosine kinase or certain G-protein coupled receptor activation elicits cell protection (without mitochondrial swelling or durable memory) by inhibiting GSK-3beta, via either PKB/Akt and mTOR/p70s6k, PKC, or PKA pathways. The convergence of these pathways via inhibition of GSK-3beta on the end effector, the permeability transition pore complex, to limit MPT induction, is the general mechanism of cardiomyocyte protection. We propose that clinical treatment strategies designed to inhibit the "master switch" kinase, GSK-3beta, to protect the permeability transition pore complex from MPT induction, would be effective to reduce the size of infarction during episodes of heart attack or stroke by preventing the death of cardiac myocytes and neurons (respectively).